(1) Field of the Invention
The present invention relates to solutions for the preservation of hearts. More particularly, this invention relates to preservation solutions for perfusing and storing a heart while awaiting transplantation, and to methods for using the preserving solution during transplantation of an organ.
(2) The Prior Art
Preservation of hearts awaiting transplantation has become common practice in many hospitals; however, the ability to make transplantations are limited to the viability of the heart. A great deal of progress has been made over the years in understanding cellular mechanisms, as well as developing new transplantation techniques for keeping organs viable, not only during storage, but also after reperfusion of these organs. As a result, organ transplantation including heart transplantation, is an established elective operation. A significant factor limiting the clinical application of organ transplantation is the deviation of viability for the organ after removal from the donor. Long term preservation of heart tissue results in two kinds of cell destruction: (1) necrosis and (2) apoptosis. Necrotic cell damage results in cell swelling with the cell organelles also swelling until the cell ruptures spilling its contents into the extra cellular space. Apoptosis (program cell death) is an organized destruction of the cell with the cellular components shrinking until nothing remains. During embryonic development, apoptosis plays an important role in tailoring various organs for adult use. Apoptosis is also present in ischemic (oxygen deprived) heart tissue as well as necrosis when preserved for 90 minutes at normal body temperatures. Apoptosis appears to be a more destructive mechanism to myocardial cells during ischemia.
The compositions of numerous of preservation solutions have been extensively studied. For example, the protective properties of cold preservation solutions was set forth in G. Tian, et al. (1991), the Journal Of Heart And Lung Transplantation (10) 975-985, where the cold preservation solutions limited the storage time of the organ. A preservation solution useful by all donor organs, both for in situ organ cooling in the donor and for cold storage after the organ is harvested is available from E.I. du Pont de Nemours and Co. under the trademark VIASPAN® and disclosed in U.S. Pat. No. 4,879,283. The solution of U.S. Pat. No. 4,879,283 has extended the preservation time of organs intended for transplantation, extending for example the viability of livers from 6 to 10 hours to over 24 hours. While the solution of U.S. Pat. No. 4,879,283 has been effective in extending the preservation time of organs intended for transplantation, cell injury still occurs. Therefore, a further reduction in cell injury and increased survival time is desirable. Another patented solution for the preservation of organs is U.S. Pat. No. 4,873,230 entitled “Composition For The Preservation Of Organs.” Yet another patented solution is U.S. Pat. No. 4,798,824 entitled “Perfusate For The Preservation Of Organs” which discloses a hydroxyethyl starch composition useful in a preservation solution.
The introduction of cyclosporin for immunosuppression during the 1980's, revived interest in transplanted organs and tissues, specifically, the liver, kidneys, pancreas, heart and lung. However, preservation methods that were successful for kidneys have not proven for these other organs, such as hearts, because the heart is more complex to transplant than kidneys. Short preservation times for the heart also necessitate two surgical teams, one for the donor and the other for the recipient. Extending preservation times for the heart would have a positive impact on the transplantation, namely, increasing organ availability, decreasing organ wastage, including organ sharing and reducing costs. Cyclosporin, a drug used to prevent rejection, has also been reported to block apoptosis in certain cell systems.
Static storage versus continuous perfusion methods has shown large differences in the length of preservation. Metabolic changes during hypothermic storage are characterized by a loss of adenosine triphosphate (ATP) and creatine phosphate (CP) which lead to disruption of ion exchange pumps and electrolyte imbalances which intensify the cell damage and prevent heart recovery. Preservation of ATP and CP levels benefits long-term heart storage. However, at least 90% of the ATP is lost in most hypothermically stored organs within 2-4 hours, but fully recover after much longer periods of preservation.
One of the major criteria for heart transplantation, after proper matching procedures are met, is that the heart must be harvested from the donor, transported and re-implanted into the recipient within a four to six hour time frame. Although extended preservation times for hearts do not seem necessary, a more reliable preservation method may extend the ranges for which hearts can be transported and received. An 18 hour barrier has existed in most experimental laboratories for large mammalian hearts with a 50% functional recovery after six hours. Although not followed for longer periods of time, the six hour time frame was used because of its clinical relevance to the initial “new-heart” functional requirements which did not involve rejection and sterility issues. It was found that at 18 hours of preservation and 4° C. with University of Wisconsin (UW) solution, no necrosis was evident in a heart but apoptosis was present. Thus, if apoptosis can be blocked, the preservation times can be extended.
It is therefore the general object of this invention to delineate the relation of apoptotic and necrotic cell death to heart preservation.
Another object of the present invention is to determine if blocking apoptosis during heart preservation extends myocardial viability and push ahead the perceived limits of cold storage for hearts, allowing a greater time from donor harvest to recipient transplantation.
Still another object of the present invention to provide preservation solutions for pulsating and storing organs while awaiting implantation, which inhibits ion exchange, extends viability of the organ and reduces damage to the cell.
Yet another object of the present invention is to provide a method for preserving hearts which extends the maximum life of the heart during transplantation.
Other object features and advantages of the invention will be apparent from the following details of the invention as more fully described.